Both Type I (T1D) and Type 2 (T2D) diabetes share a common pathophysiology - insufficient beta cell mass (BCM) to meet metabolic demands. Unfortunately, advances in diabetes are slowed by a lack of reliable methods to measure BCM in vivo. The ability to accurately track BCM would facilitate development and clinical evaluation of therapies to preserve or replace beta cells. To date, one of the most exciting emerging technologies for measuring BCM is positron emission tomography (PET) imaging using C-DTBZ, a tracer which binds to the vesicular monoamine transporter (VMAT-2) 11 expressed in beta cells in pancreatic islets. While ground-breaking studies have recently demonstrated proof of concept for C-DTBZ imaging of BCM, the applicability for human studies is limited since the 11 short half-life of C (20 min.) means that C-DTBZ clinical studies are only feasible at a limited number of centers with on-site cyclotrons. Since the PET isotope F has a 110 min. half life and has a well 18 established nationwide distribution network, an F version of DTBZ would represent an incredibly 18 powerful and widely accessible tool for the study of diabetes. We have now developed an F derivative of DTBZ (18F-FP-DTBZ or F-AV-133) and have already completed (or have in progress) all the necessary IND-enabling studies on F-FP-DTBZ. In this SBIR grant we propose to conduct the first ever clinical trial of F-FP-DTBZ in T1D and T2D patients and rapidly test the hypothesis that F-FP-DTBZ is a useful biomarker for PET imaging of BCM. 18 Successful development of a biomarker for beta cell mass (BCM) would represent a significant milestone and a large commercial opportunity for diagnostic imaging of diabetic and pre-diabetic patients. Vesicular monoamine transporter (VMAT-2) is expressed in beta cells in pancreatic islets and is the target for dihydrotetrabenazine (DTBZ). We have now synthesized a highly potent and efficacious derivative of DTBZ, AV-133 for VMAT-2 binding. 18 F-AV-133 is a first of its kind F- 18 labeled VMAT-2 targeting radiotracer that will be utilized to in a proof of concept clinical trial to image BCM in normal control and Type 1 and Type 2 diabetics. This imaging-based biomarker may represent a significant advance in diabetes management by allowing better diagnosis, disease monitoring, and therapeutic selection. Avid Radiopharmaceuticals is an experienced leader in developing new commercial PET tracers, is collaborating with world-experts on VMAT-2 imaging, and is first company with a promising F lead compound, F-AV-133, for imaging VMAT-2 expressed on beta cells. [unreadable] [unreadable] [unreadable]